SUMMARY FOR PROJECT 2 Synaptic communication is at the crux of brain function, and a key feature of AD is synaptic malfunction and synapse loss. A range of genetic and biomarker data indicate that the A? peptide triggers synaptic disease. The mechanisms by which AD-selective forms of A? damage the synapse are not well defined but have the potential to provide multiple sites for therapeutic intervention, which are distinct from regulating APP and A? themselves. Numerous studies implicate Fyn kinase in the synaptic pathophysiology of AD, with links to both A? and Tau pathology. For transgenic AD mice, genetic removal of Fyn kinase alleviates, and overexpression of Fyn exacerbates, the impairment of synaptic density and spatial memory. Our work, confirmed and extended by others, showed that Cellular Prion Protein (PrPC) acts as a cell surface binding site for toxic A? oligomers. Engagement of PrPC by A? was found to activate Fyn kinase, initiating a detrimental signaling cascade with synaptic dysfunction. Using Fyn and PrPC as molecular handles for synaptic pathology at the inner and outer surfaces of the post-synaptic density, we have sought to understand how these proteins are coupled and which signal transduction pathways are dysregulated in AD. Our Preliminary data strongly support a crucial role for mGluR5 and Fyn in AD pathophysiology. Here, we seek to validate the role of an A?o PrPC mGluR5 Fyn pathway in AD, identify biomarkers of this pathology, and explore the utility of mGluR5 agents in AD models. This project will advance the hypothesis that selectively blocking A?o mGluR5 signaling provides effective disease- modifying therapeutic strategy for AD.